Mig-6 participates in the regulation of cell senescence and retinoblastoma protein phosphorylation |
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| Affiliation: | 1. Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland;2. Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland;3. School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland;1. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA;2. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA;3. Department of Orthopaedic Surgery, Mie University School of Medicine, Mie 514, Japan;4. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;1. Department of Pharmacology, University Medical Center Göttingen, Göttingen, Germany;2. Institute of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;3. DZHK (German Centre for Cardiovascular Research) partner site Hamburg/Kiel/Lübeck, Hamburg, Germany;4. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA;5. Institut Curie, CNRS UMR 3347, INSERM U1021, Paris Sud University Centre de Recherche, Orsay, France;6. Institute of Pharmacy, University of Hamburg, Hamburg, Germany;1. Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;2. Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA |
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| Abstract: | Mitogen-inducible gene-6 (Mig-6) is a cytosolic multiadaptor protein that is best known for its role as a negative feedback regulator of epidermal growth factor receptor (EGFR) mediated signalling. Alternative roles of Mig-6 are becoming increasingly recognised. Consistently with this, Mig-6 was demonstrated to be involved in a broad spectrum of cellular events including tumour suppression which may include the induction of cellular senescence. Here, we investigated the mechanisms of Mig-6 induced premature cell senescence. Endogenous Mig-6 is poorly expressed in young fibroblasts, whilst its expression rises in cells presenting with typical features of senescence. Overexpression of Mig-6 is sufficient to trigger premature cellular senescence of early passage diploid lung fibroblasts (WI-38). Interestingly, Mig-6 overexpression reduced retinoblastoma protein (pRb) phosphorylation at the inactivating Ser249/Thr252 sites. We also found that phosphorylation of these sites in pRb is increased in the presence of the B-Raf V600E oncogenic mutation. We further show that Mig-6 overexpression reduces B-Raf V600E mediated pRb inactivation and preserves pRb function. |
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